A hereditary spastic paraplegia predominant phenotype caused by variants in the NEFL gene

Karlien Mul, Meyke I Schouten, Erica van der Looij, Dennis Dooijes, Frederic A M Hennekam, Nicolette C Notermans, Peter Praamstra, Judith van Gaalen, Erik-Jan Kamsteeg, Nienke E Verbeek, Bart P C van de Warrenburg

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INTRODUCTION: This study reports a large series of patients with a clinical picture dominated by spastic paraplegia in whom variants in the NEFL gene, a known cause for Charcot-Marie-Tooth disease, were identified.

METHODS: Index patients referred for a suspicion of hereditary spastic paraplegia (HSP) were clinically assessed and genetic analysis by next-generation sequencing was undertaken. Additional family members were clinically examined and subjected to targeted testing.

RESULTS: We identified two different heterozygous dominant variants in the NEFL gene in 25 patients from 14 families. Most of them (21/25) had a clinical diagnosis of HSP, often with a concomitant clinical diagnosis of polyneuropathy (16/21). Two patients were identified with a polyneuropathy with a pyramidal reflex pattern, but without spasticity. Two patients had isolated polyneuropathy. Out of the 21 patients with a diagnosis of HSP, two had co-occurring cerebellar signs. The c.262A > C p.(Thr88Pro) variant was detected in 13 families. Genealogical analysis showed shared ancestors or a similar geographical origin in 12, suggesting a founder effect. The other variant, c.296A > C p.(Asp99Ala), was found in only one family, in which limited segregation analysis could be performed.

DISCUSSION: Variants in the NEFL gene can cause HSP, with or without co-existing polyneuropathy, and should be included in diagnostic testing strategies for HSP patients.

Original languageEnglish
Pages (from-to)98-101
Number of pages4
JournalParkinsonism & Related Disorders
Early online date12 Sept 2020
Publication statusPublished - Nov 2020


  • Genotype-phenotype
  • Hereditary spastic paraplegia
  • NEFL gene
  • Polyneuropathy


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